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Camptothecin analogs with enhanced activity against human breast cancer cells. I. Correlation of potency with lipophilicity and persistence in the cleavage complex.

Publication ,  Journal Article
Adams, DJ; da Silva, MW; Flowers, JL; Kohlhagen, G; Pommier, Y; Colvin, OM; Manikumar, G; Wani, MC
Published in: Cancer Chemother Pharmacol
January 2006

The effect of 7-alkyl substitutions on growth inhibition in seven Camptothecin (CPT) ring systems with various groups at the ten position was evaluated in three human breast cancer cell lines that model (1) hormone-sensitive (MCF-7/wt), (2) hormone insensitive (MDA-MB-231), or (3) alkylator-resistant (MCF-7/4-hc) forms of disease. To assess the impact of persistence of cleavage complexes on antiproliferative activity, a post-exposure recovery period in drug-free medium was incorporated into the growth inhibition assay. This modification produced on average a twofold reduction in the growth inhibition endpoint (the IC50), suggesting a greater apoptotic response. The results further revealed a three log range in potency from a mean IC50 of 2 nM (7-butyl-10,11-methylenedioxy-CPT) to 2.5 microM (7-bromomethyl-10-hydryoxy-CPT). Increasing 7-alkyl chain length in six of the ten-substituted CPTs enhanced potency, which was directly correlated with persistence of topoisomerase I-induced DNA cleavage complexes in 10-hydroxy, 10-methoxy, and 10,11-methylenedioxy substituted CPTs. Modeling of the binding mode of 7-butyl-10-amino-CPT revealed a direct hydrogen bond contact for the 10-amino to the side chain of Glu-356 of Core Subdomain I of top1 in addition to known contacts found for other camptothecins. More important, residues 350-356 and 425-431 of Core Subdomain I may provide induced fit stabilization to the lipophilic alkyl moiety at the seven position.

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Published In

Cancer Chemother Pharmacol

DOI

ISSN

0344-5704

Publication Date

January 2006

Volume

57

Issue

2

Start / End Page

135 / 144

Location

Germany

Related Subject Headings

  • Tumor Cells, Cultured
  • Oncology & Carcinogenesis
  • Humans
  • Female
  • Dose-Response Relationship, Drug
  • Cell Proliferation
  • Camptothecin
  • Breast Neoplasms
  • Apoptosis
  • Antineoplastic Agents, Phytogenic
 

Citation

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Adams, D. J., da Silva, M. W., Flowers, J. L., Kohlhagen, G., Pommier, Y., Colvin, O. M., … Wani, M. C. (2006). Camptothecin analogs with enhanced activity against human breast cancer cells. I. Correlation of potency with lipophilicity and persistence in the cleavage complex. Cancer Chemother Pharmacol, 57(2), 135–144. https://doi.org/10.1007/s00280-005-0007-6
Adams, David J., Mateus Webba da Silva, James L. Flowers, Glenda Kohlhagen, Yves Pommier, O Michael Colvin, Govindarajan Manikumar, and Mansukh C. Wani. “Camptothecin analogs with enhanced activity against human breast cancer cells. I. Correlation of potency with lipophilicity and persistence in the cleavage complex.Cancer Chemother Pharmacol 57, no. 2 (January 2006): 135–44. https://doi.org/10.1007/s00280-005-0007-6.
Adams DJ, da Silva MW, Flowers JL, Kohlhagen G, Pommier Y, Colvin OM, et al. Camptothecin analogs with enhanced activity against human breast cancer cells. I. Correlation of potency with lipophilicity and persistence in the cleavage complex. Cancer Chemother Pharmacol. 2006 Jan;57(2):135–44.
Adams, David J., et al. “Camptothecin analogs with enhanced activity against human breast cancer cells. I. Correlation of potency with lipophilicity and persistence in the cleavage complex.Cancer Chemother Pharmacol, vol. 57, no. 2, Jan. 2006, pp. 135–44. Pubmed, doi:10.1007/s00280-005-0007-6.
Adams DJ, da Silva MW, Flowers JL, Kohlhagen G, Pommier Y, Colvin OM, Manikumar G, Wani MC. Camptothecin analogs with enhanced activity against human breast cancer cells. I. Correlation of potency with lipophilicity and persistence in the cleavage complex. Cancer Chemother Pharmacol. 2006 Jan;57(2):135–144.
Journal cover image

Published In

Cancer Chemother Pharmacol

DOI

ISSN

0344-5704

Publication Date

January 2006

Volume

57

Issue

2

Start / End Page

135 / 144

Location

Germany

Related Subject Headings

  • Tumor Cells, Cultured
  • Oncology & Carcinogenesis
  • Humans
  • Female
  • Dose-Response Relationship, Drug
  • Cell Proliferation
  • Camptothecin
  • Breast Neoplasms
  • Apoptosis
  • Antineoplastic Agents, Phytogenic